Abstract: To enable the application of PRS development and implementation, our eMERGE IV proposal from Partners HealthCare leverages a large biobank (>105,000 consented with genotype data on 40,000), clinical data in the electronic health records (EHR) for >4 million patients from the largest integrated health care provider in New England, advanced bioinformatics expertise, prior leadership in PRS development and state- of-the-art genetic analysis, established expertise in returning genomics results, and experience using information technology to transform clinical processes and assessing outcomes. We propose to build on our expertise to accomplish the specific aims: Aim 1 (Discovery): Hypothesis: Polygenic risks scores will allow us to stratify eMERGE subjects based on genetic risk for common complex traits. Using the largest available genomic data resources, we will calculate and validate new PRS for coronary artery disease, atrial fibrillation, type 2 diabetes, colorectal cancer and major depression across diverse ancestries. We will 1) compare and benchmark the performance of existing PRS construction methods in different ancestral groups, 2) develop novel statistical methods for robust trans-ethnic PRS prediction, and integrate PRS with established clinical risk factors and family history. We will obtain PRS from our network colleagues for an additional 15-e- phenotypes (total 20) with a goal of identifying high-risk individuals, e.g., top 2% of PRS risk Aim 2 (RiskInsight Report/ELSI): We will develop a ?Risk Insight Report? with clinical risk factors, family history, and PRS with evidence-based recommendations for high risk participants (top 2% of phenotype specific PRS distribution) for electronic clinical implementation. We will assess risk communication formats in our ELSI Sub-Aim 1: To test the impact and interpretability of two mock RiskInsight Reports summarizing PRS as either (a) dichotomous (defining the patient as high-risk vs intermediate/low risk) or (b) quantitative (providing a numerical estimate of the percentile of risk for the patient), with linked clinical recommendations in both cases. We will then assess, through surveys of diverse HCPs and patients, the extent to which the mock reports are understood by both HCPs and patients. Aim 3 (Outcomes): Hypothesis: Physicians will alter their surveillance and treatment of patients based on eCDS of RiskInsight Reports. Among HCPs for high-risk subjects, we will see at least one change in clinical care after disclosure discussions with subjects. We will recruit 2500 participants for implementation of clinical PRS in RiskInsight Reports using a SMART on FHIR app for eCDS integrated with the EHR. The primary outcome will be whether any HCP took any action within 12 months after receipt of e-CDS defined by ordering screening tests, prescribing a preventive medication, or providing lifestyle advice. We will conduct analyses of the effect of disclosing results to high risk participants to determine how personalized results changed patient outcomes in laboratory values, risk reduction behaviors, or health care utilization.